The size of a particle is critical to its ability to cross the skin barrier and therefore its ability to deliver a pharmaceutically active ingredient for the treatment of local or systemic medical conditions of the patient concerned. As particles become smaller (particularly below 100 nm), the percentage of exposed surface area of a particle in proportion to its total volume when compared to unrefined material is increased, and hence its potential efficacy is increased.
The characteristics of sub-micron particles in their application to the delivery of pharmaceutically active ingredients across the skin barrier may be summarised as follows:
Particle sizeDescriptionCharacteristics300-1000nmEmulsionBlue-white, milky liquid, reasonablephysical stability. Particles reside onskin surface → transdermaldelivery.100-300nmSub-micronBluish, translucent liquid. EnhancedEmulsionphysical stability. Particles reside onskin surface → enhanced transdermaldelivery.10-100nmMicroemulsionTranslucent-transparent liquid.Excellent physical stability. Particlesreside on skin surface → enhancedtransdermal delivery.<5nmNanoparticles/Translucent-transparent liquid.Nano-Excellent physical stability. Particlesdispersion/reside on skin surface, within stratumMicellescorneum and in hair follicles → optimaltransdermal delivery.
Because of the desirable characteristics of so called microemulsions, and sub-micron emulsions, attempts have been made to perfect the means of their manufacture. Essentially, the much higher ratio of emulsifier to disperse phase is that feature which differentiates a microemulsion from a macroemulsion. The aim is to stabilise oil phases in water phases, or vice versa. The nature of the emulsifier (or surfactant) used is clearly very important. Oil in water micro emulsions are particularly difficult to formulate and, generally speaking, simply adapting the mode, or means of homogenization, or increasing the amount of emulsifier present will not guarantee the product is a microemulsion. The choice of emulsifier is reportedly critical to the success of the formulation (BK: MicroEmulsions Theory and Practice, Prince, Leon (ed) pp 33-50, Academic Press, NY, USA, 1977).
Water in oil systems are made by blending the oil and emulsifier, with a little heat if necessary, and then adding water. The amount of water that can be added to a given system of emulsifier and oil may not always be high enough for the application in mind. In that event, it becomes necessary to try other emulsifiers. When one is found that permits the desired water uptake, it may be convenient from a processing viewpoint to add the mixture of emulsifier and oil to the water. Again, warming the system may hasten the mixing process. In systems of oil, water and emulsifier that are capable of forming microemulsions, the order of mixing does not affect the end result.
The simplest way to make an oil in water microemulsion is to blend the oil and emulsifier and then pour this liquid mixture into the water with mild stirring. Another technique is to make a crude macroemulsion of the oil and one of the emulsifiers, for example, a soap. By using low volumes of water a gel is formed. This gel is then changed into a clear solution by titration with a second surface active agent like an alcohol. This system may then be transformed into an opalescent oil in water microemulsion of the desired concentration by further addition of water. By far the most common method of making an oil in water microemulsion, especially in the trial and error stage, however, is by the so-called inversion process.
In actual practice, oils which are capable of being microemulsified, i.e. “emulsifiable oils”, as opposed to those which may be dispersed in micellar solution, invert by the slow addition of water from a fluid water in oil dispersion through a viscoelastic gel stage to a fluid oil in water microemulsion. 100% emulsifier on the weight of the oil may be employed. After careful blending, with heat if necessary, water is added to the blend in a beaker. This is done in successive, small aliquots. If the chemistry is right, a clear, transparent water in oil dispersion first forms. This is fluid. As more water is added, at about equal volumes of water and oil/emulsifier blend, the system begins to become more viscous. As more water is added, it becomes very viscous, ultimately becoming a heavy gel. At this point it is frequently helpful to apply heat to thin the gel and facilitate passage through this stage. With the addition of more water, the gel eventually thins out to a fluid oil in water microemulsion which can readily be identified by its clarity or opalescence.
The highly viscous intermediate gel stages are not microemulsions but are sometimes so called, as in the case of ringing gels used as hair pomades. These systems are actually liquid crystalline phases and occur because of the particular sequence of mixing employed in forming the microemulsion.
Given the importance of the emulsifier to the successful formulation of the microemulsion, systems have been developed to assist in selection of the emulsifier. One such system (Shiroda, K., J. Colloid Interface Sci, 24, 4 (1967)) is that based upon the temperature at which an emulsifier causes an oil in water emulsion to invert to a water in oil emulsion. It is known as the Phase Inversion Temperature (PIT) System. It provides information about various oils, phase volume relationships, and the concentration of emulsifier required. The system is established on the proposition that the hydrophilic lipophilic balance (the “HLB”) of a non-ionic surfactant changes with temperature and that the inversion of emulsion type occurs when the hydrophilic and lipophilic tendencies of the emulsifier just balance each other. No emulsion forms at this temperature. Emulsions stabilised with non-ionic agents are oil in water types at low temperature and invert to water in oil types at elevated temperature. It goes without saying that use of more than one emulsifier in a composition may positively influence the formulation of a microemulsion. PIT techniques require a significant input of energy in order to attain a sub-micron emulsion. The process requires high temperature so as to render the ethoxylated surfactant hydrophobic, whereby the oil in water emulsion becomes a water in oil emulsion, and thereafter, the conversion of the water in oil dispersion to a oil in water dispersion is effected upon subsequent cooling of the formulation. At least because of the degradative effect that heat has upon certain active ingredients, it would be desirable to reduce the energy requirements for such processes as this is likely to reduce the risk of crystallisation of poorly soluble active ingredients occurring upon normal temperature cycling of the stored product
Microemulsion technology has been the subject of relatively intense investigation since the late 1950's when hair gels using the technology were first developed.
One U.S. Pat. No. 6,333,362 (L'OREAL) describes an ultrafine foaming oil in water emulsion where the particle size of the oil particles constituting the oil phase range from 50-1000 nm. The PIT technique is used to manufacture the formulation. Example 1 describes a prior art formulation as follows:
Phase 1%dicapryl ether7.7Isocetyl stearate3.0cetearyl isononanoate4.0beheneth-94.5
Phase 2%Distilled water14.7Preservativeq.s
Phase 3%distilled waterq.s.100sodium lauryl ether sulphate5.0where the sodium lauryl ether sulphate in phase 3 acts as the foaming agent on dispensing the product from its pressurised can. To prepare the formulation phases 1 and 2 were heated separately to 60° C. and homogenised. Phase 2 was poured slowly, with stirring, onto Phase 1 and the mixture was heated as far as the phase inversion temperature, which was around 85° C. The heating was stopped and Phase 3 was poured in unheated and the mixture was allowed to cool while slow stirring was maintained.
Nanoemulsions which contain an amphiphilic lipid phase composed of phospholipids, water and oil are known in the art. These emulsions exhibit the disadvantage of being unstable on storage at conventional storage temperatures, namely between 0 and 45° C. They lead to yellow compositions and produce rancid smells which develop several days after storage. One example of such an emulsion is described in WO 03/08222 (BEIERDORF AG)
In practice there are challenges in formulating microemulsions. The point at which the composition inverts from an oil in water or water in oil formulation, respectively, to a water in oil or oil in water formulation, known as the “set point” needs to be carefully monitored. If the set point is not reached before the product is poured out, inversion will not occur, and so a microemulsion will not be achieved. High set points in particular can be difficult to achieve and maintain. Additives can be used to lower the set point but these can also have the effect of destabilising the microemulsion resulting in undesirable alteration of the viscosity of the microemulsion, cloudiness, and can also cause loss of invertible character altogether. Furthermore, although high levels of emulsifier can be desirable, on the other hand, high emulsifier content can lead to skin and eye irritation of the user.
Petrolatum, which is desirably used in dermatological compositions for its occlusive and emollient properties, is considered too difficult to incorporate in microemulsion formulations because of its viscosity.
Another ingredient which is desirable in dermatological applications is propylene glycol for its capacity as a penetration enhancer. However, it has been reported as undesirable in microemulsion technology because of its potential to disrupt or destabilise the formulation. WO 94/08603 (SMITHKLINE BEECHAM CORPORATION) teaches the avoidance of propylene glycol and other polyhydroxyl alcohol cosurfactants because of the processing and stability issues they introduce.
Another challenge in the application of microemulsions to the field of dermatology is the solubilisation of the pharmaceutically active ingredients in the formulations. Some pharmaceutically active ingredients are highly water soluble, or in the alternative are highly oil soluble. Others are sparingly soluble. A pharmaceutically active ingredient in solution provides better penetration than one in suspension and, both of these provide better penetration than a drug as a solid. In the case where a pharmaceutically active ingredient is not easily solubilised, the need for an additive such as propylene glycol which can assist in penetration, is obvious, but conversely the ease of formation of a microemulsion is diminished.
In light of the foregoing, it is an object of this invention to identify methods of formulating microemulsions and sub-micron emulsion formulations which may act as a vehicle for the delivery of a pharmaceutically active ingredient across the skin barrier for cosmetic or therapeutic purposes. It is a secondary object to achieve a means of incorporating one or more microemulsion disrupting substances, such as petrolatum and/or propylene glycol into such a microemulsion or sub-micron emulsion at the same time maintaining the viscosity, appearance, stability and efficacy of the formulation.
Any discussion of documents, devices, acts or knowledge in this specification is included to explain the context of the invention. It should not be taken as admission that any of the information formed part of the prior art base or the common general knowledge in the relevant art on or before the priority date of the present subject matter.